Hetero isonipecotic modulators of vanilloid VR1 receptor

ABSTRACT

This invention is directed to vanilloid receptor VR1 ligands. More particularly, this invention relates to hetero isonipecotic amides that are potent modulators of VR1 which are useful for the treatment and prevention of disease conditions in mammals.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No.60/583,326, filed Jun. 28, 2004.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

The research and development of the invention described below was notfederally sponsored.

BACKGROUND OF THE INVENTION

This invention is directed to novel vanilloid receptor VR1 ligands. Moreparticularly, this invention relates to novel hetero isonipecotic amidesthat are potent modulators of VR1.

Noxious chemical, thermal and mechanical stimuli excite peripheral nerveendings of small diameter sensory neurons (nociceptors) in sensoryganglia (e. g., dorsal root, nodose and trigeminal ganglia) and initiatesignals that are perceived as pain. These neurons are crucial for thedetection of harmful or potentially harmful stimuli (heat) and tissuedamage (local tissue acidosis and/or stretch) that arise from changes inthe extracellular space during inflammatory or ischaemic conditions(Wall, P. D., and Melzack, R., Textbook of Pain, 1994, New York:Churchill Livingstone). Nociceptors transduce noxious stimuli intomembrane depolarization that triggers action potential, conducts theaction potential from the sensory sites to the synapses in the CNS, andconversion of action potentials invokes a perception of pain,discomfort, and appropriate mechanical/physical protective reflexes. Atthe molecular level, nociception is carried out by ion channels orreceptors. Plant derived vanilloid compounds (capsaicin and itsultrapotent analog, resiniferatoxin, etc.) are known to selectivelydepolarize nociceptors and elicit sensations of burning pain—thesensation that is typically obtained by hot chili peppers. Therefore,capsaicin mimics the action of physiological/endogenous stimuli thatactivates the “nociceptive pathway”. Recent advances in pain biologyhave identified receptors for vanilloids, protons (i.e., acidicsolutions), and for heat. Because nociceptors are involved with unwantedpain and inflammatory conditions in human beings and animals, modulationof their nociceptive pathway is important in palliative and othertherapies.

Walpole and colleagues at Sandoz reported on the first competitiveantagonist of the sensory neuron excitants capsaicin andresineriferatoxin (Walpole, C. S. J. et. al., J. Med. Chem. 1994, 37,1942). Subsequently, capsazepine has been shown to be a vanilloidreceptor antagonist.

SUMMARY OF THE INVENTION

The invention is directed to compounds of formula (I)

wherein

-   -   is a 4 to 8 membered cyclic heteroalkyl group bonded to the rest        of the molecule through a ring nitrogen atom and optionally        containing 1-2 heteroatoms in addition to said ring nitrogen        atom, wherein the optional 1-2 additional heteroatoms are        independently selected from the group consisting of N, O and S;        or a 5 to 10 membered heteroaryl group bonded to the rest of the        molecule through a ring nitrogen atom and selected from the        group consisting of dihydroquinoline, tetrahydroquinoline,        dihydroisoquinoline, tetrahydroisoquinoline, benzimidazole,        imidazole, imidazoline, indazole, indole, indoline, isoindole,        isoindoline, pyrazole, pyrrole, and triazole;    -   Y is bonded to    -   at a substitutable atom and is independently selected from the        group consisting of hydrogen; hydroxyl; R¹; R¹O—; R¹S—; CF₃O—;        R¹S(O)—; R¹SO₂—; -LCOX; C₆₋₁₀aryl; a 3 to 7 membered cyclic        heteroalkanyl containing from 1 to 3 heteroatoms wherein said        heteroatoms independently are N, O or S; and a 5 to 10 membered        heteroaryl selected from the group consisting of benzofuran,        benzimidazole, benzisoxazole, benzthiazole, benzothiophene,        benzoxazole, cinnoline, furan, imidazole, imidazoline, indazole,        indole, indoline, indolizine, isobenzofuran, isoindole,        isoindoline, isoquinoline, isothiazole, isoxazole,        naphthyridine, oxadiazole, oxazole, pthalazine, pteridine,        purine, pyran, pyrazine, pyrazole, pyridazine, pyridine,        pyrimidine, pyrrole, pyrrolizine, quinoline, quinolizine,        quinazoline, quinoxaline, tetrazole, thiadiazole, thiazole,        thiophene, triazine, and triazole;    -   n is an integer from 0 to 4;    -   Ar is phenyl; naphthyl; a 5-6 membered heteroaryl ring selected        from the group consisting of furan, imidazole, isothiazole,        isoxazole, oxadiazole, oxazole, pyran, pyrazine, pyrazole,        pyridazine, pyrrole, tetrazole, thiadiazole, triazine, and        triazole; or a fused 5,6 or 6,6 heteroaryl selected from the        group consisting of benzimidazole, benzisoxazole, benzofuran,        benzoxazole, benzthiazole, benzothiophene, cinnoline, indazole,        indole, indoline, indolizine, isobenzofuran, isoindole,        isoindoline, isoquinoline, naphthyridine, pthalazine, pteridine,        pyrrolizine, quinoline, and quinolizine; wherein Ar is        optionally substituted with one to four substituents        independently selected from the group consisting of halogen; R¹;        fluorinated C₁₋₁₀alkyl; phenyl; amino; cyano; CF₃O—; a 3        membered cyclic heteroalkyl containing 1 heteroatom that is N, O        or S wherein said 3 membered cyclic heteroalkyl is optionally        substituted with a substituent that is halogen, R¹, fluorinated        C₁₋₁₀ alkyl, amino, cyano, CF₃O—, R¹O—, R¹S—, R¹SO₂—, R¹S(O)—,        R¹SO₂NH—, or -LCOX; a 4 to 5 membered cyclic heteroalkyl        containing 1-3 heteroatoms that independently are N, O or S        wherein said 4 to 5 membered cyclic heteroalkyl is optionally        substituted with 1 to 2 substituents that independently are        halogen, R¹, fluorinated C₁₋₁₀alkyl, amino, cyano, CF₃O—, R¹O—,        R¹S—, R¹SO₂—, R¹S(O)—, R¹SO₂NH—, or -LCOX; a 6 to 7 membered        cyclic heteroalkyl containing 1-3 heteroatoms that independently        are N, O or S wherein said 6 to 7 membered cyclic heteroalkyl is        optionally substituted with 1 to 3 substituents that        independently are halogen, R¹, fluorinated C₁₋₁₀alkyl, amino,        cyano, CF₃O—, R¹O—, R¹S—, R¹SO₂—, R¹S(O)—, R¹SO₂NH—, or -LCOX; a        heteroaryl wherein said heteroaryl is cinnoline, furan,        imidazole, indazole, indole, indoline, indolizine,        isobenzofuran, isoindole, isoindoline, isoquinoline,        isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole,        pthalazine, pteridine, pyran, pyrazine, pyrazole, pyridazine,        pyridine, pyrimidine, pyrrole, pyrrolizine, quinoline,        quinolizine, quinazoline, quinoxaline, tetrazole, thiadiazole,        triazine, or triazole wherein said heteroaryl is optionally        substituted with 1 to 3 substituents that independently are        halogen, R¹, fluorinated C₁₋₁₀alkyl, amino, cyano, CF₃O—, R¹O—,        R¹S—, R¹SO₂—, R¹S(O)—, R¹SO₂NH—, or -LCOX;; hydroxyl;; R¹O—;        R¹S—; R¹SO₂—; R¹S(O)—; R¹SO₂NH—; -LCOX; and C₆₋₁₀aryl;    -   R¹ is C₁₋₁₀alkyl;    -   L is —NH—, a direct bond, —O—, or —CH₂—;    -   X is H, R¹, HO, R¹O—, R¹S—, —NH₂, R¹NH—, or (R¹)₂N—; and    -   enantiomers, diastereomers, tautomers, solvates, and        pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the following underlined terms are intended to have thefollowing meanings:

“C_(a-b)” (where a and b are integers) refers to a radical containingfrom a to b carbon atoms inclusive. For example, C₁₋₃ denotes a radicalcontaining 1, 2 or 3 carbon atoms.

“Fluorinated alkyl” refers to a saturated branched or straight chainhydrocarbon radical derived by removal of 1 hydrogen atom from theparent alkane; the parent alkane contains from 1 to 6 carbon atoms with1 or more hydrogen atoms substituted with fluorine atoms up to andincluding substitution of all hydrogen atoms with fluorine. Preferredfluorinated alkyls include trifluoromethyl substituted alkyls andperfluorinated alkyls; more preferred fluorinated alkyls includetrifluoromethyl, perfluoroethyl, 2,2,2-trifluoroethyl, perfluoropropyl,3,3,3-trifluoroprop-1-yl, 3,3,3-trifluoroprop-2-yl,1,1,1,3,3,3-hexafluoroprop-2-yl; a particularly preferred fluorinatedalkyl is trifluoromethyl.

“Fluorinated alkanyloxy” refers to a radical derived from a fluorinatedalkyl radical attached to an oxygen atom with the oxygen atom having oneopen valence for attachment to a parent structure.

“Alkyl:” refers to a saturated or unsaturated, branched, straight-chainor cyclic monovalent hydrocarbon radical derived by the removal of onehydrogen atom from a single carbon atom of a parent alkane, alkene oralkyne. Typical alkyl groups include, but are not limited to, methyl;ethyls such as ethanyl, ethenyl, ethynyl; propyls such as propan-1-yl,propan-2-yl , cyclopropan-1-yl, prop-1-en-1-yl, prop-1-en-2-yl,prop-2-en-1-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1-yl,prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butyls such as butan-1-yl,butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl,but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl,but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl,cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl,but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like. Wherespecific levels of saturation are intended, the nomenclature “alkanyl”,“alkenyl” and/or “alkynyl” is used, as defined below. In preferredembodiments, the alkyl groups are (C₁₋₈) alkyl, with (C₁₋₃) beingparticularly preferred.)

“Alkanyl:” refers to a saturated branched, straight-chain or cyclicmonovalent hydrocarbon radical derived by the removal of one hydrogenatom from a single carbon atom of a parent alkane. Typical alkanylgroups include, but are not limited to, methanyl; ethanyl; propanylssuch as propan-1-yl, propan-2-yl, cyclopropan-1-yl, etc.; butyanyls suchas butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl,cyclobutan-1-yl, etc.; and the like. In preferred embodiments, thealkanyl groups are (C₁₋₈) alkanyl, with (C₁₋₃) being particularlypreferred.

“Alkenyl:” refers to an unsaturated branched, straight-chain or cyclicmonovalent hydrocarbon radical having at least one carbon-carbon doublebond derived by the removal of one hydrogen atom from a single carbonatom of a parent alkene. The radical may be in either the cis or transconformation about the double bond(s). Typical alkenyl groups include,but are not limited to, ethenyl; propenyls such as prop-1-en-1-yl,prop-1-en-2-yl, prop-2-en-1-yl, prop-2-en-2-yl, cycloprop-1-en-1-yl;cycloprop-2-en-1-yl; butenyls such as but-1-en-1-yl, but-1-en-2-yl,2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-2-yl,buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl,cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl, etc.; and the like. Inpreferred embodiments, the alkenyl group is (C₂₋₈) alkenyl, with (C₂₋₃)being particularly preferred.

“Alkynyl:” refers to an unsaturated branched, straight-chain or cyclicmonovalent hydrocarbon radical having at least one carbon-carbon triplebond derived by the removal of one hydrogen atom from a single carbonatom of a parent alkyne. Typical alkynyl groups include, but are notlimited to, ethynyl; propynyls such as prop-1-yn-1-yl, prop-2-yn-1-yl,etc.; butynyls such as but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl,etc.; and the like. In preferred embodiments, the alkynyl group is(C₂₋₈) alkynyl, with (C₂₋₃) being particularly preferred.

“Alkyldiyl:” refers to a saturated or unsaturated, branched,straight-chain or cyclic divalent hydrocarbon radical derived by theremoval of one hydrogen atom from each of two different carbon atoms ofa parent alkane, alkene or alkyne, or by the removal of two hydrogenatoms from a single carbon atom of a parent alkane, alkene or alkyne.The two monovalent radical centers can form bonds with the same ordifferent atoms. Typical alkyldiyls include, but are not limited tomethandiyl; ethyldiyls such as ethan-1,1-diyl, ethan-1,2-diyl,ethen-1,1-diyl, ethen-1,2-diyl; propyldiyls such as propan-1,1-diyl,propan-1,2-diyl, propan-2,2-diyl, propan-1,3-diyl, cyclopropan-1,1-diyl,cyclopropan-1,2-diyl, prop-1-en-1,1-diyl, prop-1-en-1,2-diyl,prop-2-en-1,2-diyl, prop-1-en-1,3-diyl, cycloprop-1-en-1,2-diyl,cycloprop-2-en-1,2-diyl, cycloprop-2-en-1,1-diyl, prop-1-yn-1,3-diyl,etc.; butyldiyls such as, butan-1,1-diyl, butan-1,2-diyl,butan-1,3-diyl, butan-1,4-diyl, butan-2,2-diyl,2-methyl-propan-1,1-diyl, 2-methyl-propan-1,2-diyl, cyclobutan-1,1-diyl;cyclobutan-1,2-diyl, cyclobutan-1,3-diyl, but-1-en-1,1-diyl,but-1-en-1,2-diyl, but-1-en-1,3-diyl, but-1-en-1,4-diyl,2-methyl-prop-1-en-1,1-diyl, 2-methylprop-2-en-1,1-diyl,buta-1,3-dien-1,1-diyl, buta-1,3-dien-1,2-diyl, buta-1,3-dien-1,3-diyl,buta-1,3-dien-1,4-diyl, cyclobut-1-en-1,2-diyl, cyclobut-1-en-1,3-diyl,cyclobut-2-en-1,2-diyl, cyclobuta-1,3-dien-1,2-diyl,cyclobuta-1,3-dien-1,3-diyl, but-1-yn-1,3-diyl, but-1-yn-1,4-diyl,buta-1,3-diyn-1,4-diyl, etc.; and the like. Where specific levels ofsaturation are intended, the nomenclature alkandiyl, alkendiyl and/oralkyndiyl is used. In preferred embodiments, the alkyldiyl group is(C₁₋₈) alkyldiyl, with (C₁₋₈) being particularly preferred. Alsopreferred are saturated acyclic alkandiyl radicals in which the radicalcenters are at the terminal carbons, e.g., methandiyl; ethan-1,2-diyl;propan-1,3-diyl; butan-1,4-diyl; and the like (also referred to asalkylenos, as defined infra).

“Vic Alkyldiyl:” refers to a saturated or unsaturated, branched,straight-chain or cyclic hydrocarbon radical having two adjacentmonovalent radical centers derived by the removal of one hydrogen atomfrom each of two adjacent carbon atoms of a parent alkane, alkene oralkyne. The two monovalent radical centers can form bonds with the sameor different atom(s). Typical vic alkyldiyls include, but are notlimited to vic ethyldiyls such as ethan-1,2-diyl, ethen-1,2-diyl; vicpropyldiyls such as propan-1,2-diyl, cyclopropan-1,2-diyl,prop-1-en-1,2-diyl, prop-2-en-1,2-diyl, cycloprop-1-en-1,2-diyl, etc.;vic butyldiyls such as butan-1,2-diyl, 2-methyl-propan-1,2-diyl,cyclobutan-1,2-diyl, but-1-en-1,2-diyl, cyclobut-1-en-1,2-diyl,buta-1,3-dien-1,2-diyl, cyclobuta-1,3-dien-1,2-diyl, but-3-yn-1,2-diyl,etc.; and the like. Where specific levels of saturation are intended,the nomenclature vic alkandiyl, vic alkendiyl and/or vic alkyndiyl isused. In preferred embodiments, the vic alkyldiyl group is (C₂₋₈) vicalkyldiyl, with (C₂₋₃) being particularly preferred.

“Gem Alkyldiyl:” refers to a saturated or unsaturated, branched,straight-chain or cyclic hydrocarbon radical having one divalent radicalcenter derived by the removal of two hydrogen atoms from a single carbonatom of a parent alkane, alkene or alkyne. The divalent radical centerforms bonds with two different atoms. Typical gem alkyldiyls include,but are not limited to gem methanyidiyl; gem ethyldiyls such asethan-1,1-diyl,ethen-1,1-diyl; gem propyldiyls such as propan-1,1-diyl,propan-2,2-diyl, cyclopropan-1,1-diyl, prop-1-en-1,1-diyl,cycloprop-2-en-1,1-diyl, prop-2-yn-1,1-diyl, etc.; butyldiyls such asbutan-1,1-diyl, butan-2,2-diyl, 2-methyl-propan-1,2-diyl,cyclobutan-1,1-diyl, but-1-en-1,1-diyl, 2-methyl-prop-1-en-1,1-diyl,2-methyl-prop-2-en-1,1-diyl, cyclobut-2-en-1,1-diyl,buta-1,3-dien-1,1-diyl, etc.; and the like. Where specific levels ofsaturation are intended, the nomenclature gem alkandiyl, gem alkendiyland/or gem alkyndiyl is used. In preferred embodiments, the gemalkyldiyl group is (C₁₋₆) gem alkyldiyl, with (C₁₋₃) being particularlypreferred.

“Alkyleno:” refers to a saturated or unsaturated, straight-chain orbranched acyclic bivalent hydrocarbon bridge radical derived by theremoval of one hydrogen atom from each of the two terminal carbon atomsof an acyclic parent alkane, alkene or alkyne. Typical alkyleno groupsinclude, but are not limited to, methano; ethylenos such as ethano,etheno, ethyno; propylenos such as propano, propeno, prop-1,2-dieno,propyno, etc.; butylenos such as butano, 2-methyl-propano, but-1-eno,but-2-eno, 2-methyl-prop-1-eno, 2-methanylidene-propano, but-1,3-dieno,but-1-yno, but-2-yno, but-1,3-diyno, etc.; and the like. Where specificlevels of saturation are intended, the nomenclature alkano, alkenoand/or alkyno is used. In preferred embodiments, the alkyleno group is(C₁₋₈) alkyleno, with (C₁₋₃) being particularly preferred. Alsopreferred are straight-chain saturated alkano radicals, e.g., methano,ethano, propano, butano, and the like.

“Alkylidene:” refers to a saturated or unsaturated, branched,straight-chain or cyclic divalent hydrocarbon radical derived by removalof two hydrogen atoms from the same carbon atom of a parent alkane,alkene or alkyne. The divalent radical center forms a double bond with asingle atom. Typical alkylidene radicals include, but are not limitedto, methanylidene, ethylidenes such as ethanylidene, ethenylidene;propylidenes such as propan-1-ylidene, propan-2-ylidene,cyclopropan-1-ylidene, prop-1-en-1-ylidene, prop-2-en-1-ylidene,cycloprop-2-en-1-ylidene, etc.; butylidenes such as butan-1-ylidene,butan-2-ylidene, 2-methyl-propan-1-ylidene, cyclobutan-1-ylidene,but-1-en-1-ylidene, but-2-en-1-ylidene, but-3-en-1-ylidene,buta-1,3-dien-1-ylidene; cyclobut-2-en-1-ylidene, etc.; and the like.Where specific levels of saturation are intended, the nomenclaturealkanylidene, alkenylidene and/or alkynylidene is used. In preferredembodiments, the alkylidene group is (C₁₋₈) alkylidene, with (C₁₋₃)being particularly preferred. Also preferred are acyclic saturatedalkanylidene radicals in which the divalent radical is at a terminalcarbon, e.g., methanylidene, ethan-1-ylidene, propan-1-ylidene,butan-1-ylidene, 2-methyl-propan-1-ylidene, and the like.

“Alkylidyne:” refers to a saturated or unsaturated, branched orstraight-chain trivalent hydrocarbon radical derived by removal of threehydrogen atoms from the same carbon atom of a parent alkane, alkene oralkyne. The trivalent radical center forms a triple bond with a singleatom. Typical alkylidyne radicals include, but are not limited to,methanylidyne; ethanylidyne; propylidynes such as propan-1-ylidyne,prop-2-en-1-ylidyne, prop-2-yn-1-ylidyne; butylidynes such asbutan-1-ylidyne, 2-methyl-propan-1-ylidyne, but-2-en-1-ylidyne,but-3-en-1-ylidyne, buta-2,3-dien-1-ylidyne, but-2-yn-1-ylidyne,but-3-yn-1-ylidyne, etc.; and the like. Where specific levels ofsaturation are intended, the nomenclature alkanylidyne, alkenylidyneand/or alkynylidyne is used. In preferred embodiments, the alkylidynegroup is (C₁₋₈) alkylidyne, with (C₁₋₃) being particularly preferred.Also preferred are saturated alkanylidyne radicals, e.g., methanylidyne,ethanylidyne, propan-1-ylidyne, butan-1-ylidyne,2-methyl-propan-1-ylidyne, and the like.

“Heteroalkyl, Heteroalkanyl, Heteroalkenyl, Heteroalkynyl,Heteroalkylidene, Heteroalkylidyne, Heteroalkyldiyl, Vic Heteralkyldiyl,Gem Heteroalkyldiyl, Heteroalkyleno and Heteroalkyldiylidene:” refer toalkyl, alkanyl, alkenyl, alkynyl, alkylidene, alkylidyne, alkyldiyl, vicalkyldiyl, gem alkyldiyl, alkyleno and alkyldiylidene radicals,respectively, in which one or more carbon atoms (and any necessaryassociated hydrogen atoms) are independently replaced with the same ordifferent heteroatoms (including any necessary hydrogen or other atoms).Typical heteroatoms to replace the carbon atom(s) include, but are notlimited to, N, P, O, S, Si, etc. Preferred heteroatoms are O, N and S.Thus, heteroalkyl, heteroalkanyl, heteroalkenyl, heteroalkynyl,heteroalkylidene, heteroalkylidyne, heteroalkyldiyl, vicheteroalkyldiyl, gem heteroalkyldiyl, heteroalkyleno andheteroalkyldiylidene radicals can contain one or more of the same ordifferent heteroatomic groups, including, by way of example and notlimitation, epoxy (—O—), epidioxy (—O—O—), thioether (—S—), epidithio(—SS—), epoxythio (—O—S—), epoxyimino (—O—NR′—), imino (—NR′—), biimmino(—NR′—NR′—), azino (═N—N═), azo (—N═N—), azoxy (—N—O—N—), azimino(—NR′—N═N—), phosphano (—PH—), λ⁴-sulfano (—SH₂-), sulfonyl (—S(O)₂—),and the like, where each R′ is independently hydrogen or (C₁-C₆) alkyl.

“Parent Aromatic Ring System:” refers to an unsaturated cyclic orpolycyclic ring system having a conjugated Tr electron system.Specifically included within the definition of “parent aromatic ringsystem” are fused ring systems in which one or more rings are aromaticand one or more rings are saturated or unsaturated, such as, forexample, indane, indene, phenalene, etc. Typical parent aromatic ringsystems include, but are not limited to, aceanthrylene, acenaphthylene,acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene,fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene,s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene,ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene,phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene,rubicene, triphenylene, trinaphthalene, and the like

“Aryl:” refers to a monovalent aromatic hydrocarbon radical derived bythe removal of one hydrogen atom from a single carbon atom of a parentaromatic ring system. Typical aryl groups include, but are not limitedto, radicals derived from aceanthrylene, acenaphthylene,acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene,fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene,s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene,ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene,phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene,rubicene, triphenylene, trinaphthalene, and the like. In preferredembodiments, the aryl group is (C₅₋₂₀ ) aryl, with (C₅₋₁₀) beingparticularly preferred. Particularly preferred aryl groups are phenyland naphthyl groups.

“Arylalkyl:” refers to an acyclic alkyl group in which one of thehydrogen atoms bonded to a carbon atom, typically a terminal carbonatom, is replaced with an aryl radical. Typical arylalkyl groupsinclude, but are not limited to, benzyl, 2-phenylethan-1-yl,2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl,2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and thelike. Where specific alkyl moieties are intended, the nomenclaturearylalkanyl, arylakenyl and/or arylalkynyl is used. [In preferredembodiments, the arylalkyl group is (C₆₋₂₆) arylalkyl, e.g., thealkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (C₁₋₆) andthe aryl moiety is (C₅₋₂₀). In particularly preferred embodiments thearylalkyl group is (C₆₋₁₃), e.g., the alkanyl, alkenyl or alkynyl moietyof the arylalkyl group is (C₁₋₃) and the aryl moiety is (C₅₋₁₀). Evenmore preferred arylalkyl groups are phenylalkanyls.

“Alkanyloxy:” refers to a saturated branched, straight-chain or cyclicmonovalent hydrocarbon alcohol radical derived by the removal of thehydrogen atom from the hydroxide oxygen of the alcohol. Typicalalkanyloxy groups include, but are not limited to, methanyl; ethanyloxy;propanyloxy groups such as propan-1-yloxy (CH₃CH₂CH₂O—), propan-2-yloxy((CH₃)₂CHO—), cyclopropan-1-yloxy, etc.; butyanyloxy groups such asbutan-1-yloxy, butan-2-yloxy, 2-methyl-propan-1-yloxy,2-methyl-propan-2-yloxy, cyclobutan-1-yloxy, etc.; and the like. Inpreferred embodiments, the alkanyloxy groups are (C₁₋₈) alkanyloxygroups, with (C₁₋₃) being particularly preferred.

“Parent Heteroaromatic Ring System:” refers to a parent aromatic ringsystem in which one or more carbon atoms are each independently replacedwith a heteroatom. Typical heteratoms to replace the carbon atomsinclude, but are not limited to, N, P, O, S, Si etc. Specificallyincluded within the definition of “parent heteroaromatic ring systems”are fused ring systems in which one or more rings are aromatic and oneor more rings are saturated or unsaturated, such as, for example,arsindole, chromane, chromene, indole, indoline, xanthene, etc. Typicalparent heteroaromatic ring systems include, but are not limited to,arsindole, carbazole, β-carboline, chromane, chromene, cinnoline, furan,imidazole, indazole, indole, indoline, indolizine, isobenzofuran,isochromene, isoindole, isoindoline, isoquinoline, isothiazole,isoxazole, naphthyridine, oxadiazole, oxazole, perimidine,phenanthridine, phenanthroline, phenazine, phthalazine, pteridine,purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine,pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline,tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and thelike.

“Heteroaryl:” refers to a monovalent heteroaromatic radical derived bythe removal of one hydrogen atom from a single atom of a parentheteroaromatic ring system. Typical heteroaryl groups include, but arenot limited to, radicals derived from acridine, arsindole, carbazole,β-carboline, chromane, chromene, cinnoline, furan, imidazole, indazole,indole, indoline, indolizine, isobenzofuran, isochromene, isoindole,isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine,oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline,phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole,pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline,quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole,thiophene, triazole, xanthene, and the like. In preferred embodiments,the heteroaryl group is a 5-20 membered heteroaryl, with 5-10 memberedheteroaryl being particularly preferred. Specific preferred heteroarylsfor the present invention are quinoline, isoquinoline, pyridine,pyrimidine, furan, thiophene and imidazole.

“Substituted:” refers to a radical in which one or more hydrogen atomsare each independently replaced with the same or differentsubstituent(s). Typical substituents include, but are not limited to,—X, —R, —O⁻—, ═—O, —OR, —O—OR, —SR, —S⁻, ═S, —NRR, ═NR, —CX₃, —CN, —OCN,—SCN, —NCO, —NCS, —NO, —NO₂, ═N₂, —N₃, —NHOH, —S(O)₂O⁼—, —S(O)₂OH,—S(O)₂R, —P(O)(O⁻)₂, —P(O)(OH)₂, —C(O)R, —C(O)X, —C(S)R, —C(S)X,—C(O)OR, —C(O)O⁻, —C(S)OR, —C(O)SR, —C(S)SR, —C(O)NRR, —C(S)NRR and—C(NR)NRR, where each X is independently a halogen (preferably —F, —Clor —Br) and each R is independently —H, alkyl, alkanyl, alkenyl,alkynyl, alkylidene, alkylidyne, aryl, arylalkyl, arylheteroalkyl,heteroaryl, heteroarylalkyl or heteroaryl-heteroalkyl, as definedherein. Preferred substituents include hydroxy, halogen, C₁₋₈alkyl,C₁₋₈alkanyloxy, fluorinated alkanyloxy, fluorinated alkyl,C₁₋₈alkylthio, C₃₋₈cycloalkyl, C₃₋₈cycloalkanyloxy, nitro, amino,C₁₋₈alkylamino, C₁₋₈dialkylamino, C₃₋₈cycloalkylamino, cyano, carboxy,C₁₋₇alkanyloxycarbonyl, C₁₋₇alkylcarbonyloxy, formyl, carbamoyl, phenyl,aroyl, carbamoyl, amidino, (C₁₋₈alkylamino)carbonyl, (arylamino)carbonyland aryl(C₁₋₈alkyl)carbonyl.

“Aroyl” refers to arylacyl substituents.

“Acyl” refers to alkylcarbonyl substituents. With reference tosubstituents, the term “independentlyl” means that when more than one ofsuch substituent is possible, such substituents may be the same ordifferent from each other.

Throughout this disclosure, the terminal portion of the designated sidechain is described first, followed by the adjacent functionality towardthe point of attachment. Thus, for example, a“phenylC₁₋₆alkanylaminocarbonylC₁₋₆alkyl” substituent refers to a groupof the formula

The invention is directed compounds of formula (I)

wherein

-   -   is a 4 to 8 membered cyclic heteroalkyl group bonded to the rest        of the molecule through a ring nitrogen atom and optionally        containing 1-2 heteroatoms in addition to said ring nitrogen        atom, wherein the optional 1-2 additional heteroatoms are        independently selected from the group consisting of N, O and S;        or a 5 to 10 membered heteroaryl group bonded to the rest of the        molecule through a ring nitrogen atom and selected from the        group consisting of dihydroquinoline, tetrahydroquinoline,        dihydroisoquinoline, tetrahydroisoquinoline, benzimidazole,        imidazole, imidazoline, indazole, indole, indoline, isoindole,        isoindoline, pyrazole, pyrrole, and triazole;    -   Y is bonded to    -   at a substitutable atom and is independently selected from the        group consisting of hydrogen; hydroxyl; R¹; R¹O—; R¹S—;

CF₃O—; R¹S(O)—; R¹SO₂—; -LCOX; C₆₋₁₀aryl; a 3 to 7 membered cyclicheteroalkanyl containing from 1 to 3 heteroatoms wherein saidheteroatoms independently are N, O or S; and a 5 to 10 memberedheteroaryl selected from the group consisting of benzofuran,benzimidazole, benzisoxazole, benzthiazole, benzothiophene, benzoxazole,cinnoline, furan, imidazole, imidazoline, indazole, indole, indoline,indolizine, isobenzofuran, isoindole, isoindoline, isoquinoline,isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, pthalazine,pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine,pyrimidine, pyrrole, pyrrolizine, quinoline, quinolizine, quinazoline,quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazine, andtriazole;

-   -   n is an integer from 0 to 4;    -   Ar is phenyl; naphthyl; a 5-6 membered heteroaryl ring selected        from the group consisting of furan, imidazole, isothiazole,        isoxazole, oxadiazole, oxazole, pyran, pyrazine, pyrazole,        pyridazine, pyrrole, tetrazole, thiadiazole, triazine, and        triazole; or a fused 5,6 or 6,6 heteroaryl selected from the        group consisting of benzimidazole, benzisoxazole, benzofuran,        benzoxazole, benzthiazole, benzothiophene, cinnoline, indazole,        indole, indoline, indolizine, isobenzofuran, isoindole,        isoindoline, isoquinoline, naphthyridine, pthalazine, pteridine,        pyrrolizine, quinoline, and quinolizine; wherein Ar is        optionally substituted with one to four substituents        independently selected from the group consisting of halogen; R¹;        fluorinated C₁₋₁₀alkyl; phenyl; amino; cyano; fluorinated        C₁₋₁₀alkyl; a 3 membered cyclic heteroalkyl containing 1        heteroatom that is N, O or S wherein said 3 membered cyclic        heteroalkyl is optionally substituted with a substituent that is        halogen, R¹, fluorinated C₁₋₁₀alkyl, amino, cyano, R¹O—, R¹S—,        R¹SO₂—, R¹S(O)—, R¹SO₂NH—, or -LCOX; a 4 to 5 membered cyclic        heteroalkyl containing 1-3 heteroatoms that independently are N,        O or S wherein said 4 to 5 membered cyclic heteroalkyl is        optionally substituted with 1 to 2 substituents that        independently are halogen, R¹, fluorinated C₁₋₁₀alkyl, amino,        cyano, CF₃O—, R¹O—, R¹S—, R¹SO₂—, R¹S(O)—, R¹SO₂NH—, or -LCOX; a        6 to 7 membered cyclic heteroalkyl containing 1-3 heteroatoms        that independently are N, O or S wherein said 6 to 7 membered        cyclic heteroalkyl is optionally substituted with 1 to 3        substituents that independently are halogen, R¹, fluorinated        C₁₋₁₀alkyl, amino, cyano, R¹O—, R¹S—, R¹SO₂—, R¹S(O)—, R¹SO₂NH—,        or -LCOX; a heteroaryl wherein said heteroaryl is cinnoline,        furan, imidazole, indazole, indole, indoline, indolizine,        isobenzofuran, isoindole, isoindoline, isoquinoline,        isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole,        pthalazine, pteridine, pyran, pyrazine, pyrazole, pyridazine,        pyridine, pyrimidine, pyrrole, pyrrolizine, quinoline,        quinolizine, quinazoline, quinoxaline, tetrazole, thiadiazole,        triazine, or triazole wherein said heteroaryl is optionally        substituted with 1 to 3 substituents that independently are        halogen, R¹, fluorinated C₁₋₁₀alkyl, amino, cyano, CF₃O—, R¹O—,        R¹S—, R¹SO₂—, R¹S(O)—, R¹SO₂NH—, or -LCOX;; hydroxyl;; R¹O—;        R¹S—; R¹SO₂—; R¹S(O)—; R¹SO₂NH—; -LCOX; and C₆₋₁₀aryl;    -   R¹ is C₁₋₁₀alkyl;    -   L is —NH—, a direct bond, —O—, or —CH₂—;    -   X is H, R¹, HO, R¹O—, R¹S—, —NH₂, R¹NH—, or (R¹)₂N—; and    -   enantiomers, diastereomers, tautomers, solvates, and        pharmaceutically acceptable salts thereof.

Embodiments of the present invention are compounds of formula (I) inwhich

-   -   (h) Y is OH;    -   (i) Y is methylcarbonyl;    -   (j) Y is methyl;    -   (k) n is 0;    -   (l) n is 1;    -   (m) Ar is phenyl;    -   (n) Ar is naphthyl;    -   (o) Ar is substituted with 1-2 substituents independently        selected from the group consisting of halogen, R¹, R¹O—,        fluorinated C₁₋₁₀alkyl, phenyl, and fluorinated C₁₋₁₀alkyl;    -   (p) Ar is substituted with 1-2 substituents independently        selected from the group consisting of methyl, phenyl, CF₃—, F,        and CH₃O—; and    -   (q) combinations of (a) through (p), above.

Thus, an embodiment of the present invention include a compound offormula (I) wherein Ar is phenyl optionally substituted with 1-2substituents independently selected from the group consisting ofhalogen, R¹, R¹O—, fluorinated C₁₋₁₀alkyl, phenyl, and fluorinatedC₁₋₁₀alkyl.

Another embodiment of the present invention is a compound of formula (I)wherein

is piperidin-1-yl and n is 1.

Another embodiment of the present invention is a compound of formula (I)wherein n is 1 and Y is OH or methylcarbonyl.

Another embodiment of the present invention is a compound of formula (I)wherein Ar is biphenyl, methylphenyl or dimethylphenyl;

Another embodiment of the present invention is a compound of formula (I)selected from the group consisting of:

-   -   Thiomorpholin-4-yl-(1-o-tolyl-piperidin-4-yl)-methanone;    -   [1-(2,3-Dimethyl-phenyl)-piperidin-4-yl]-(4-hydroxy-piperidin-1-yl)-methanone;    -   (1-Biphenyl-3-yl-piperidin-4-yl)-morpholin-4-yl-methanone;    -   [1-(3-Fluoro-4-methyl-phenyl)-piperidin-4-yl]-thiomorpholin-4-yl-methanone    -   Morpholin-4-yl-[1-(3-trifluoromethyl-phenyl)-piperidin-4-yl]-methanone;    -   [1-(3,4-Dimethyl-phenyl)-piperidin-4-yl]-thiomorpholin-4-yl-methanone;    -   [1-(2,3-Dimethyl-phenyl)-piperidin-4-yl]-thiomorpholin-4-yl-methanone;    -   [1-(3,4-Dimethyl-phenyl)-piperidin-4-yl]-(4-hydroxy-piperidin-1-yl)-methanone;    -   [1-(3,4-Dimethyl-phenyl)-piperidin-4-yl]-piperidin-1-yl-methanone;    -   [1-(3-Fluoro-4-methyl-phenyl)-piperidin-4-yl]-piperidin-1-yl-methanone;    -   (4-Hydroxy-piperidin-1-yl)-(1-o-tolyl-piperidin-4-yl)-methanone;    -   [1-(3,4-Dimethyl-phenyl)-piperidin-4-yl]-morpholin-4-yl-methanone;    -   Morpholin-4-yl-(1-o-tolyl-piperidin-4-yl)-methanone;    -   [1-(2,3-Dimethyl-phenyl)-piperidin-4-yl]-piperidin-1-yl-methanone;    -   [1-(3,5-Difluoro-phenyl)-piperidin-4-yl]-morpholin-4-yl-methanone;    -   [1-(2,3-Dimethyl-phenyl)-piperidin-4-yl]-thiazolidin-3-yl-methanone;    -   (1-Naphthalen-1-yl-piperidin-4-yl)-piperidin-1-yl-methanone;    -   [1-(3,5-Difluoro-phenyl)-piperidin-4-yl]-thiomorpholin-4-y1-methanone;    -   [1-(3-Fluoro-4-methyl-phenyl)-piperidin-4-yl]-morpholin-4-yl-methanone;

[1-(3,5-Difluoro-phenyl)-piperidin-4-yl]-piperidin-1-yl-methanone;

(1-Biphenyl-3-yl-piperidin-4-yl)-thiomorpholin-4-yl-methanone;

[1-(3-Fluoro-4-methyl-phenyl)-piperidin-4-yl]-(4-hydroxy-piperidin-1-yl)-methanone;

[1-(3,5-Difluoro-phenyl)-piperidin-4-yl]-(4-hydroxy-piperidin-1-yl)-methanone;

-   -   (1-Naphthalen-1-yl-piperidin-4-yl)-thiazolidin-3-yl-methanone;    -   Azepan-1-yl-(1-o-tolyl-piperidin-4-yl)-methanone;    -   Piperidin-1-yl-(1-o-tolyl-piperidin-4-yl)-methanone;    -   [1-(3-Methoxy-phenyl)-piperidin-4-yl]-morpholin-4-yl-methanone;    -   Piperidin-1-yl-[1-(3-trifluoromethyl-phenyl)-piperidin-4-yl]-methanone;    -   Piperidin-1-yl-(1-m-tolyl-piperidin-4-yl)-methanone;    -   1-[4-(1-Biphenyl-3-yl-piperidine-4-carbonyl)-piperazin-1-yl]-ethanone;    -   1-{4-[1-(2,3-Dimethyl-phenyl)-piperidine-4-carbonyl]-piperazin-1-yl}-ethanone;    -   Morpholin-4-yl-(1-m-tolyl-piperidin-4-yl)-methanone;    -   (1-Biphenyl-3-yl-piperidin-4-yl)-piperidin-1-yl-methanone;    -   [1-(3-Methoxy-phenyl)-piperidin-4-yl]-thiomorpholin-4-yl-methanone;    -   [1-(2,3-Dimethyl-phenyl)-piperidin-4-yl]-(2,6-dimethyl-piperidin-1-yl)-methanone;    -   [1-(2,3-Dimethyl-phenyl)-piperidin-4-yl]-(3-hydroxy-pyrrolidin-1-yl)-methanone;    -   Thiazolidin-3-yl-(1-o-tolyl-piperidin-4-yl)-methanone;    -   Pyrrolidin-1-yl-(1-o-tolyl-piperidin-4-yl)-methanone;    -   (1-Isoquinolin-1-yl-piperidin-4-yl)-morpholin-4-yl-methanone;    -   [1-(3,6-Dimethyl-pyrazin-2-yl)-piperidin-4-yl]-morpholin-4-yl-methanone;    -   Morpholin-4-yl-(1-naphthalen-1-yl-piperidin-4-yl)-methanone;    -   [1-(2,3-Dimethyl-phenyl)-piperidin-4-yl]-morpholin-4-yl-methanone;    -   Morpholin-4-yl-[1-(3-trifluoromethyl-phenyl)-piperidin-4-yl]-methanone;    -   (1-Naphthalen-1-yl-piperidin-4-yl)-thiomorpholin-4-yl-methanone;    -   (1-Isoquinolin-1-yl-piperidin-4-yl)-thiomorpholin-4-yl-methanone;    -   Thiomorpholin-4-yl-(1-m-tolyl-piperidin-4-yl)-methanone;    -   Thiomorpholin-4-yl-[1-(3-trifluoromethyl-phenyl)-piperidin-4-yl]-methanone;    -   [1-(3,6-Dimethyl-pyrazin-2-yl)-piperidin-4-yl]-thiomorpholin-4-yl-methanone;    -   (4-Hydroxy-piperidin-1-yl)-(1-naphthalen-1-yl-piperidin-4-yl)-methanone;    -   (4-Hydroxy-piperidin-1-yl)-(1-isoquinolin-1-yl-piperidin-4-yl)-methanone;    -   (1-Biphenyl-3-yl-piperidin-4-yl)-(4-hydroxy-piperidin-1-yl)-methanone;    -   (1-Isoquinolin-1-yl-piperidin-4-yl)-piperidin-1-yl-methanone;    -   Piperidin-1-yl-(1-m-tolyl-piperidin-4-yl)-methanone;    -   [1-(3-Methoxy-phenyl)-piperidin-4-yl]-piperidin-1-yl-methanone;    -   Piperidin-1-yl-[1-(3-trifluoromethyl-phenyl)-piperidin-4-yl]-methanone;    -   [1-(3,6-Dimethyl-pyrazin-2-yl)-piperidin-4-yl]-piperidin-1-yl-methanone;    -   [1-(2,3-Dimethyl-phenyl)-piperidin-4-yl]-pyrrolidin-1-yl-methanone;    -   (1-Naphthalen-1-yl-piperidin-4-yl)-pyrrolidin-1-yl-methanone;    -   (1-Biphenyl-3-yl-piperidin-4-yl)-pyrrolidin-1-yl-methanone;    -   (1-Isoquinolin-1-yl-piperidin-4-yl)-pyrrolidin-1-yl-methanone;    -   [1-(3-Fluoro-4-methyl-phenyl)-piperidin-4-yl]-pyrrolidin-1-yl-methanone;    -   Pyrrolidin-1-yl-(1-m-tolyl-piperidin-4-yl)-methanone;    -   [1-(3,5-Difluoro-phenyl)-piperidin-4-yl]-pyrrolidin-1-yl-methanone;    -   [1-(3,6-Dimethyl-pyrazin-2-yl)-piperidin-4-yl]-pyrrolidin-1-yl-methanone;    -   [1-(3-Methoxy-phenyl)-piperidin-4-yl]-pyrrolidin-1-yl-methanone;    -   Pyrrolidin-1-yl-[1-(3-trifluoromethyl-phenyl)-piperidin-4-yl]-methanone;    -   (1-Biphenyl-3-yl-piperidin-4-yl)-thiazolidin-3-yl-methanone;    -   (1-Isoquinolin-1-yl-piperidin-4-yl)-thiazolidin-3-yl-methanone;    -   Thiazolidin-3-yl-(1-m-tolyl-piperidin-4-yl)-methanone;    -   [1-(3,5-Difluoro-phenyl)-piperidin-4-yl)-thiazolidin-3-yl-methanone;    -   [1-(3,6-Dimethyl-pyrazin-2-yl)-piperidin-4-yl]-thiazolidin-3-yl-methanone;    -   [1-(3-Methoxy-phenyl)-piperidin-4-yl]-thiazolidin-3-yl-methanone;    -   Thiazolidin-3-yl-[1-(3-trifluoromethyl-phenyl)-piperidin-4-yl]-methanone;    -   (2,6-Dimethyl-piperidin-1-yl)-(1-naphthalen-1-yl-piperidin-4-yl)-methanone;    -   (1-Biphenyl-3-yl-piperidin-4-yl)-(2,6-dimethyl-piperidin-1-yl)-methanone;    -   (2,6-Dimethyl-piperidin-1-yl)-(1-o-tolyl-piperidin-4-yl)-methanone;    -   (2,6-Dimethyl-piperidin-1-yl)-(        1-m-tolyl-piperidin-4-yl)-methanone;    -   [1-(3,5-Difluoro-phenyl)-piperidin-4-yl]-(2,6-dimethyl-piperidin-1-yl)-methanone;    -   (2,6-Dimethyl-piperidin-1-yl)-[1-(3,6-dimethyl-pyrazin-2-yl)-piperidin-4-yl]-methanone;    -   (2,6-Dimethyl-piperidin-1-yl)-[1-(3-methoxy-phenyl)-piperidin-4-yl]-methanone;    -   (2,6-Dimethyl-piperidin-1-yl)-[1-(3-trifluoromethyl-phenyl)-piperidin-4-yl]-methanone;    -   (3-Hydroxy-pyrrolidin-1-yl)-(1-naphthalen-1-yl-piperidin-4-yl)-methanone;    -   (1-Biphenyl-3-yl-piperidin-4-yl)-(3-hydroxy-pyrrolidin-1-yl)-methanone;    -   (3-Hydroxy-pyrrolidin-1-yl)-(1-isoquinolin-1-yl-piperidin-4-yl)-methanone;    -   (3-Hydroxy-pyrrolidin-1-yl)-(1-o-tolyl-piperidin-4-yl)-methanone;    -   [1-(3-Fluoro-4-methyl-phenyl)-piperidin-4-yl]-(3-hydroxy-pyrrolidin-1-yl)-methanone;    -   [1-(3,6-Dimethyl-pyrazin-2-yl)-piperidin-4-yl]-(3-hydroxy-pyrrolidin-1-yl)-methanone;    -   Azepan-1-yl-[1-(2,3-dimethyl-phenyl)-piperidin-4-yl]-methanone;    -   Azepan-1-yl-(1-naphthalen-1-yl-piperidin-4-yl)-methanone;    -   Azepan-1-yl-(1-biphenyl-3-yl-piperidin-4-yl)-methanone;    -   Azepan-1-yl-(1-isoquinolin-1-yl-piperidin-4-yl)-methanone;    -   Azepan-1-yl-[1-(3-fluoro-4-methyl-phenyl)-piperidin-4-yl]-methanone;    -   Azepan-1-yl-(1-m-tolyl-piperidin-4-yl)-methanone;    -   Azepan-1-yl-[1-(3,5-difluoro-phenyl)-piperidin-4-yl]-methanone;    -   Azepan-1-yl-[1-(3-methoxy-phenyl)-piperidin-4-yl]-methanone;    -   Azepan-1-yl-[1-(3-trifluoromethyl-phenyl)-piperidin-4-yl]-methanone;    -   Azepan-1-yl-[1-(3,6-dimethyl-pyrazin-2-yl)-piperidin-4-yl]-methanone;    -   1-[4-(1-Isoquinolin-1-yl-piperidine-4-carbonyl)-piperazin-1-yl]-ethanone;    -   1-[4-(1-o-Tolyl-piperidine-4-carbonyl)-piperazin-1-yl]-ethanone;    -   1-{4-[1-(3-Fluoro-4-methyl-phenyl)-piperidine-4-carbonyl]-piperazin-1-yl}-ethanone;    -   1-[4-(1-m-Tolyl-piperidine-4-carbonyl)-piperazin-1-yl]-ethanone;    -   1-{4-[1-(3,5-Difluoro-phenyl)-piperidine-4-carbonyl]-piperazin-1-yl}-ethanone;    -   1-{4-[1-(3-Methoxy-phenyl)-piperidine-4-carbonyl]-piperazin-1-yl}-ethanone;    -   1-{4-[1-(3-Trifluoromethyl-phenyl)-piperidine-4-carbonyl]-piperazin-1-yl}-ethanone;    -   1-{4-[1-(3,6-Dimethyl-pyrazin-2-yl)-piperidine-4-carbonyl]-piperazin-1-yl}-ethanone;    -   1-[1-(2,3-Dimethyl-phenyl)-piperidine-4-carbonyl]-pyrrolidine-2-carboxylic        acid amide;    -   1-(1-Naphthalen-1-yl-piperidine-4-carbonyl)-pyrrolidine-2-carboxylic        acid amide;    -   1-(1-Biphenyl-3-yl-piperidine-4-carbonyl)-pyrrolidine-2-carboxylic        acid amide;    -   1-(1-Isoquinolin-1-yl-piperidine-4-carbonyl)-pyrrolidine-2-carboxylic        acid amide;    -   1-(1-o-Tolyl-piperidine-4-carbonyl)-pyrrolidine-2-carboxylic        acid amide;    -   1-[1-(3-Fluoro-4-methyl-phenyl)-piperidine-4-carbonyl]-pyrrolidine-2-carboxylic        acid amide;    -   1-(1-m-Tolyl-piperidine-4-carbonyl)-pyrrolidine-2-carboxylic        acid amide;    -   1-[1-(3-Methoxy-phenyl)-piperidine-4-carbonyl]-pyrrolidine-2-carboxylic        acid amide;    -   1-[1-(3-Trifluoromethyl-phenyl)-piperidine-4-carbonyl]-pyrrolidine-2-carboxylic        acid amide;    -   1-[1-(3,5-Difluoro-phenyl)-piperidine-4-carbonyl]-pyrrolidine-2-carboxylic        acid amide;    -   1-[1-(3,6-Dimethyl-pyrazin-2-yl)-piperidine-4-carbonyl]-pyrrolidine-2-carboxylic        acid amide;    -   Azetidin-1-yl-[1-(2,3-dimethyl-phenyl)-piperidin-4-yl]-methanone;    -   Azetidin-1-yl-(1-naphthalen-1-yl-piperidin-4-yl)-methanone;    -   Azetidin-1-yl-(1-isoquinolin-1-yl-piperidin-4-yl)-methanone;    -   Azetidin-1-yl-(1-biphenyl-3-yl-piperidin-4-yl)-methanone;    -   Azetidin-1-yl-(1-o-tolyl-piperidin-4-yl)-methanone;    -   Azetidin-1-yl-[1-(3-fluoro-4-methyl-phenyl)-piperidin-4-yl]-methanone;    -   Azetidin-1-yl-(1-m-tolyl-piperidin-4-yl)-methanone;    -   Azetidin-1-yl-[1-(3-methoxy-phenyl)-piperidin-4-yl]-methanone;    -   Azetidin-1-yl-[1-(3-trifluoromethyl-phenyl)-piperidin-4-yl]-methanone;    -   Azetidin-1-yl-[1-(3,5-difluoro-phenyl)-piperidin-4-yl]-methanone;    -   Azetidin-1-yl-[1-(3,6-dimethyl-pyrazin-2-yl)-piperidin-4-yl]-methanone;    -   (2,6-Dimethyl-morpholin-4-yl)-[1-(2,3-dimethyl-phenyl)-piperidin-4-yl]-methanone;    -   (3,4-Dihydro-2H-quinolin-1-yl)-[1-(2,3-dimethyl-phenyl)-piperidin-4-yl]-methanone;    -   [1-(2,3-Dimethyl-phenyl)-piperidin-4-yl]-(4-ethyl-piperazin-1-yl)-methanone.

The compounds of the present invention may also be present in the formof pharmaceutically acceptable salts. For use in medicine, the salts ofthe compounds of this invention refer to non-toxic “pharmaceuticallyacceptable salts” (Ref. International J. Pharm., 1986, 33, 201-217; J.Pharm. Sci., January 1997, 66, 1, 1). Other salts well known to those inthe art may, however, be useful in the preparation of compoundsaccording to this invention or of their pharmaceutically acceptablesalts. Representative organic or inorganic acids include, but are notlimited to, hydrochloric, hydrobromic, hydriodic, perchloric, sulfuric,nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic,maleic, fumaric, malic, tartaric, citric, benzoic, mandelic,methanesulfonic, hydroxyethanesulfonic, benzenesulfonic, oxalic, pamoic,2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic,salicylic, saccharinic or trifluoroacetic acid. Representative organicor inorganic bases include, but are not limited to, basic or cationicsalts such as benzathine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine, procaine, aluminum, calcium, lithium,magnesium, potassium, sodium and zinc.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds that are readily convertible invivo into the required compound. Thus, in the methods of treatment ofthe present invention, the term “administering” shall encompass thetreatment of the various disorders described with the compoundspecifically disclosed or with a compound which may not be specificallydisclosed, but which converts to the specified compound in vivo afteradministration to the patient. Conventional procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

Where the compounds according to this invention have at least one chiralcenter, they may accordingly exist as enantiomers. Where the compoundspossess two or more chiral centers, they may additionally exist asdiastereomers. It is to be understood that all such isomers and mixturesthereof are encompassed within the scope of the present invention.Furthermore, some of the crystalline forms for the compounds may existas polymorphs and as such are intended to be included in the presentinvention. In addition, some of the compounds may form solvates withwater (i.e., hydrates) or common organic solvents, and such solvates arealso intended to be encompassed within the scope of this invention.

Where the processes for the preparation of the compounds according tothe invention give rise to mixture of stereoisomers, these isomers maybe separated by conventional techniques such as preparativechromatography. The compounds may be prepared in racemic form, orindividual enantiomers may be prepared either by enantiospecificsynthesis or by resolution. The compounds may, for example, be resolvedinto their component enantiomers by standard techniques, such as theformation of diastereomeric pairs by salt formation with an opticallyactive acid, such as (−)-di-p-toluoyl-d-tartaric acid and/or(+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallizationand regeneration of the free base. The compounds may also be resolved byformation of diastereomeric esters or amides, followed bychromatographic separation and removal of the chiral auxiliary.Alternatively, the compounds may be resolved using a chiral HPLC column.

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, 1991. The protectinggroups may be removed at a convenient subsequent stage using methodsknown from the art.

Even though the compounds of the present invention (including theirpharmaceutically, acceptable salts and pharmaceutically acceptablesolvates) can be administered alone, they will generally be administeredin admixture with a pharmaceutical carrier, excipient or diluentselected with regard to the intended route of administration andstandard pharmaceutical or veterinary practice. Thus, the presentinvention is directed to pharmaceutical and veterinary compositionscomprising compounds of Formula (I) and one or more pharmaceuticallyacceptable carriers, excipients or diluents.

By way of example, in the pharmaceutical and veterinary compositions ofthe present invention, the compounds of the present invention may beadmixed with any suitable binder(s), lubricant(s), suspending agent(s),coating agent(s), and/or solubilising agent(s).

Tablets or capsules of the compounds may be administered singly or twoor more at a time, as appropriate. It is also possible to administer thecompounds in sustained release formulations.

Alternatively, the compounds of Formula (I) can be administered byinhalation or in the form of a suppository or pessary, or they may beapplied topically in the form of a lotion, solution, cream, ointment ordusting powder. An alternative means of transdermal administration is byuse of a skin patch. For example, they can be incorporated into a creamconsisting of an aqueous emulsion of polyethylene glycols or liquidparaffin. They can also be incorporated, at a concentration of between 1and 10% by weight, into an ointment consisting of a white wax or whitesoft paraffin base together with such stabilizers and preservatives asmay be required.

For some applications, preferably the compositions are administeredorally in the form of tablets containing excipients such as starch orlactose, or in capsules or ovules either alone or in admixture withexcipients, or in the form of elixirs, solutions or suspensionscontaining flavoring or coloring agents.

The compositions (as well as the compounds alone) can also be injectedperenterally, for example intracavernosally, intravenously,intramuscularly or subcutaneously. In this case, the compositions willcomprise a suitable carrier or diluent.

For parenteral administration, the compositions are best used in theform of a sterile aqueous solution which may contain other substances,for example enough salts or monosaccharides to make the solutionisotonic with blood.

For buccal or sublingual administration the compositions may beadministered in the form of tablets or lozenges which can be formulatedin a conventional manner.

By way of further example, pharmaceutical and veterinary compositionscontaining one or more of the compounds of the invention describedherein as the active ingredient can be prepared by intimately mixing thecompound or compounds with a pharmaceutical carrier according toconventional pharmaceutical compounding techniques. The carrier may takea wide variety of forms depending upon the desired route ofadministration (e.g., oral, parenteral). Thus for liquid oralpreparations such as suspensions, elixirs and solutions, suitablecarriers and additives include water, glycols, oils, alcohols, flavoringagents, preservatives, stabilizers, coloring agents and the like; forsolid oral preparations, such as powders, capsules and tablets, suitablecarriers and additives include starches, sugars, diluents, granulatingagents, lubricants, binders, disintegrating agents and the like. Solidoral preparations may also be coated with substances such as sugars orbe enteric-coated so as to modulate the major site of absorption. Forparenteral administration, the carrier will usually consist of sterilewater and other ingredients may be added to increase solubility orpreservation. Injectable suspensions or solutions may also be preparedutilizing aqueous carriers along with appropriate additives.

Advantageously, compounds of the present invention may be administeredin a single daily dose, or the total daily dosage may be administered individed doses of two, three or four times daily. Furthermore, compoundsfor the present invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal skinpatches well known to those skilled in that art. To be administered inthe form of a transdermal delivery system, the dosage administrationwill, of course, be continuous rather than intermittent throughout thedosage regimen.

A therapeutically effective amount for use of the instant compounds or apharmaceutical composition thereof comprises a dose range of from about0.001 mg to about 1,000 mg, in particular from about 0.1 mg to about 500mg or, more particularly from about 1 mg to about 250 mg of activeingredient per day for an average (70 kg) human.

For oral administration, a pharmaceutical composition is preferablyprovided in the form of tablets containing, 0.01, 0.05, 0.1, 0.5, 1.0,2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100,150, 200, 250 and 500 milligramsof the active ingredient for the symptomatic adjustment of the dosage tothe subject to be treated.

It is also apparent to one skilled in the art that the therapeuticallyeffective dose for active compounds of the invention or a pharmaceuticalcomposition thereof will vary according to the desired effect.Therefore, optimal dosages to be administered may be readily determinedand will vary with the particular compound used, the mode ofadministration, the strength of the preparation, and the advancement ofthe disease condition. In addition, factors associated with theparticular subject being treated, including subject age, weight, dietand time of administration, will result in the need to adjust the doseto an appropriate therapeutic level. The above dosages are thusexemplary of the average case. There can, of course, be individualinstances where higher or lower dosage ranges are merited, and such arewithin the scope of this invention.

Compounds of this invention may be administered in any of the foregoingcompositions and dosage regimens or by means of those compositions anddosage regimens established in the art whenever use of the compounds ofthe invention as vanilloid receptor modulators is required for a subjectin need thereof.

The invention also provides a pharmaceutical or veterinary pack or kitcomprising one or more containers filled with one or more of theingredients of the pharmaceutical and veterinary compositions of theinvention. Optionally associated with such container(s) can be a noticein the form prescribed by a governmental agency regulating themanufacture, use or sale of pharmaceuticals or biological products,which notice reflects approval by the agency of manufacture, use or salefor human administration. As modulators of the vanilloid VR1 ionchannel, the compounds of Formula (I) are useful in methods for treatingor preventing a disease or condition in a mammal which disease orcondition is affected by the modulation of one or more vanilloidreceptors.

As modulators of the vanilloid VR1 ion channel, the compounds of Formula(I) are useful in methods for treating or preventing a disease orcondition in a mammal which disease or condition is affected by themodulation of one or more vanilloid receptors. Such methods comprisesadministering to a mammal in need of such treatment or prevention atherapeutically effective amount of a compound, salt or solvate ofFormula (I). In particular, the compounds of Formula (I) are useful forin methods for preventing or treating a chronic- or acute-pain causingdiseases or conditions and pulmonary dysfunction, and more particularly,in treating diseases or conditions that cause inflammatory pain, burningpain, itch or urinary incontinence, and chronic obstructive pulmonarydisease.

By way of example only, the compounds of Formula (I) are useful fortreating diseases and conditions selected from the group consisting ofosteoarthritis, rheumatoid arthritis, fibromyalgia, migraine, headache,toothache, burn, sunburn, snake bite (in particular, venomous snakebite), spider bite, insect sting, neurogenic bladder, benign prostatichypertrophy, interstitial cystitis, urinary tract infection, cough,asthma, chronic obstructive pulmonary disease, rhinitis, contactdermatitis/hypersensitivity, itch, eczema, anxiety, panic disorders,pharyngitis, mucositis, enteritis, cellulites, peripheral neuropathy,bilateral peripheral neuropathy, diabetic neuropathy, postherpeticneuralgia, trigeminal neuralgia, causalgia, sciatic neuritis, mandibularjoint neuralgia, peripheral neuritis, polyneuritis, stump pain, phantomlimb pain, bony fractures, post-operative ileus, irritable bowelsyndrome, inflammatory bowel diseases such as Crohn's Disease andulcerative colitis, cholecystitis, pancreatitis, postmastectomy painsyndrome, oral neuropathic pain, Charcot's pain, reflex sympatheticdystrophy, Guillain-Barre syndrome, meralgia paresthetica, burning-mouthsyndrome, optic neuritis, postfebrile neuritis, migrating neuritis,segmental neuritis, Gombault's neuritis, neuronitis, cervicobrachialneuralgia, cranial neuralgia, geniculate neuralgia, glossopharyngialneuralgia, migrainous neuralgia, idiopathic neuralgia, intercostalsneuralgia, mammary neuralgia, Morton's neuralgia, nasociliary neuralgia,occipital neuralgia, red neuralgia, Sluder's neuralgia, splenopalatineneuralgia, supraorbital neuralgia, vidian neuralgia, sinus headache,tension headache, labor, childbirth, intestinal gas, menstruation, hotflash, cancer, and trauma.

While the present invention comprises compositions comprising one ormore of the compounds of Formula (I), the present invention alsocomprises compositions comprising intermediates used in the manufactureof compounds of Formulae (I).

GENERAL SYNTHETIC METHODS

Compounds of formula (I) can be prepared by methods known to those whoare skilled in the art. The following reaction schemes are only meant torepresent examples of the invention and are in no way meant to be alimit of the invention.

The compounds of formula 1, wherein Ar, HET, and Yn are defined asabove, may be synthesized as outlined by the general synthetic routeillustrated in Scheme 1. In the first step, treatment of a commerciallyavailable isonipecotate ester 11 is coupled to an aromatic halide (ArX)to afford the N-aryl isonipecotic acid III. These reactions aregenerally performed in the presence of a palladium catalyst, anappropriate phosphine ligand, a solvent such as THF, a base such assodium t-butoxide, and at a temperature of 25° C. to 150° C., preferablyat 50-70° C. The next step involves treatment of acid III with a reagentsuch as oxalyl chloride, in a solvent such as methylene chloride, toprepare the reactive acid chloride intermediate IV. Treatment of theresulting acid chloride IV with an appropriate amine V provides thedesired final compound 1. These reactions are generally performed in thepresence of a solvent, such as methylene chloride, and a base, such astriethylamine, at a temperature of 0° C. to 150° C., preferably at 25°C. The aryl halides ArX, and amine reagents V, are either commerciallyavailable or can be prepared by methods known to those skilled in theart.

An alternative route to compounds of general formula I is illustrated inScheme 2. Treatment of isonipecotic acid VI with an appropriate amineprotecting group (PG) reagent, such as benzyl chloroformate, providesthe N-protected isonipecotic acid VII. Treatment of the acid VII withoxalyl chloride, in the presence of a solvent such as methylenechloride, provides the reactive acid chloride intermediate VIII.Treatment of the resulting acid chloride VIII with an appropriate amineV provides the amide IX. These reactions are generally performed in thepresence of a solvent, such as methylene chloride, and a base, such astriethylamine, at a temperature of 0° C. to 150° C., preferably from 0°C.-25° C. Removal of the amino protecting group (PG) under standardprocedures provides the isonipecotic amide X. Coupling of an aromatichalide (ArX) to isonipecotic amide X affords the desired final productI. These reactions are generally performed in the presence of apalladium catalyst, an appropriate phosphine ligand, a solvent such asTHF, a base such as sodium t-butoxide, and at a temperature of 25° C. to150° C., preferably at 50-70° C. The aryl halides ArX, and aminereagents V, are either commercially available or can be prepared bymethods known to those skilled in the art.

General Procedure A for N-Aryl Isonipecotic Acids

To a solution of aromatic halide (bromide or iodide) (0.1 mmol) in THF(1 mL) was added palladium acetate (2.3 mg, 0.001 (1%) mmol) and2-(di-t-butylphosphino)biphenyl (6 mg, 0.002 (2%) mmol). The resultingsolution was stirred at 25° C. for 5 minutes, then ethyl isonipecotate(1 mmol) and sodium t-butoxide (2.2 mmol) was added. The resultingmixture was stirred at 25° C. for 2 hours and then heated at 65° C. for12 hours. Water (3 mL) was added and the resulting mixture was heated at50° C. until there was no evidence of ester remaining. The crude mixturewas extracted with ethyl acetate, the aqueous layer was acidified by theaddition of 1M HCl, and the resulting acidic aqueous layer was extractedwith ethyl acetate. The organic layer was dried over anhydrous sodiumsulfate and concentrated in vacuo to provide the desired N-arylisonipecotic acid without further purification.

General Procedure B for N-Aryl Isonipecotic Amides

To a solution of N-aryl isonipecotic acid (0.2 mmol) in dichloromethane(1 mL) was added a 2 M solution oxalyl chloride (0.2 mL) indichloromethane. The resulting mixture was stirred at 25° C. for 4 hr,concentrated in vacuo, and then re-dissolved in dichloromethane (0.2mL). The resulting solution was added to a mixture of an appropriatesecondary amine (0.2 mmol) and triethylamine (0.5 mmol) indichloromethane (0.5 mL). The combined solution was stirred at 25° C.for 16 hours, poured into water, and extracted with dichloromethane. Thecombined organic layers were washed sequentially with 1 M HCl, 2 MNa₂CO₃, then dried over anhydrous sodium sulfate, and concentrated invacuo. The resulting crude product was purified by preparative TLC usinga 3:1 hexane/ethyl acetate solvent gradient to provide the desiredN-aryl isonipecotic amides.

EXAMPLE 1

(1-o-Tolyl-piperidin-4-yl)-thiomorpholin-4-yl-methanone

The title compound was prepared from commercially available ethylisonipecotate, o-tolyl bromide as the aryl halide, and thiomorpholine asthe secondary amine utilizing general procedures A and B describedabove. ¹H NMR (300 MHz, CDCl₃) δ 7.19-7.13 (m, 2H), 7.00-6.95 (m, 2H),3.95 (m, 2H), 3.82 (m, 2H), 3.21 (m, 1H), 3.17 (m, 1H), 2.71-2.54 (m,7H), 2.30 (s, 3H), 2.09 (dd, J=3.6, 13.1 Hz, 1H), 2.00 (dd, J=3.6, 12.0Hz, 1H), 1.79 (m, 1H), 1.75 (m, 1H). ESI MS: 305.3 (MH⁺).

EXAMPLE 2

[1-(2,3-Dimethyl-phenyl)-piperidin-4-yl]-(4-hydroxy-piperidin-1-yl)-methanone

The title compound was prepared from commercially available ethylisonipecotate, 2,3-dimethylbromobenzene as the aryl halide, and4-hydroxypiperidine as the secondary amine utilizing general proceduresA and B described above. ¹H NMR (300 MHz, CDCl₃) δ 7.06 (d, J=7.7 Hz,1H), 6.90 (d, J=7.7 Hz, 2H), 4.12 (m, 1H), 3.96 (m, 1H), 3.83 (m, 1H),3.33-3.13 (m, 4H), 2.70-2.61 (m, 3H), 2.27 (s, 3H), 2.22 (s, 3H),2.12-1.43 (m, 8H). ESI MS: 317.4 (MH⁺).

EXAMPLE 3

(1-Biphenyl-3-yl-piperidin-4-yl)-morpholin-4-yl-methanone

The title compound was prepared from commercially available ethylisonipecotate, m-biphenyl bromide as the aryl halide, and morpholine asthe secondary amine utilizing general procedures A and B describedabove. ¹H NMR (300 MHz, CDCl₃) δ 7.59-7.30 (m, 6H), 7.14 (t, J=2.0 Hz,1H), 7.07 (d, J=7.7 Hz, 1H), 6.94 (dd, J=2.0, 7.6 Hz, 1H), 3.85 (m, 1H),3.80 (m, 1H), 3.63-3.55 (m, 8H), 2.80 (dt, J=2.6, 12.2 Hz, 2H), 2.60(tt, J=2.8, 11.4 Hz, 1H), 2.07 (dd, J=3.8, 12.8 Hz, 1H), 2.01 (dd,J=4.0, 12.0 Hz, 1H), 1.85 (m, 1H), 1.81 (m, 1H). ESI MS: 351.4 (MH⁺).

EXAMPLE 4

[1-(3-Fluoro-4-methyl-phenyl)-piperidin-4-yl]-thiomorpholin-4-yl-methanone

The title compound was prepared from commercially available ethylisonipecotate, 3-fluoro-4-methylbromobenzene as the aryl halide, andthiomorpholine as the secondary amine utilizing general procedures A andB described above. ¹H NMR (300 MHz, CDCl₃) ¹H NMR (CDCl₃) δ 7.02 (dd,J=7.2, 9.2 Hz, 1H), 6.63-6.55 (m, 2H), 3.90 (m, 2H), 3.80 (m, 2H), 3.70(m, 1H), 3.65 (m, 1H), 2.75-2.51 (m, 7H), 2.17 (d, J=1.6 Hz, 3H), 2.01(dd, J=3.3, 13.4 Hz, 1H), 1.91 (dd, J=4.0, 11.4Hz, 1H), 1.80 (m, 1H),1.76 (m, 1H). ESI MS: 323.3 (MH⁺).

EXAMPLE 5

[1-(3-Trifluoromethyl-phenyl)-piperidin-4-yl-morpholin-4-yl-methanone

The title compound was prepared from commercially available ethylisonipecotate, 3-(trifluoromethyl)-bromobenzene as the aryl halide, andmorpholine as the secondary amine utilizing general procedures A and Bdescribed above. ¹H NMR (300 MHz, CDCl₃) ¹H NMR (CDCl₃) δ 7.34 (dd,J=7.6, 8.6 Hz, 1H), 7.11-7.05 (m, 3H), 3.80 (m, 1H), 3.76 (m, 1H),3.70-3.54 (m, 8H), 2.81 (dt, J=2.7, 12.4 Hz, 2H), 2.67-2.57 (m, 1H),2.09 (dd, J=4.2, 13.4 Hz, 1H), 2.00 (dd, J=4.0, 11.7 Hz, 1H), 1.85 (m,1H), 1.81 (m, 1H). ESI MS: 343.4 (MH⁺).

EXAMPLE 6

[1-(3,4-Dimethyl-phenyl)-piperidin-4-yl]-thiomorpholin-4-yl-methanone

The title compound was prepared from commercially available ethylisonipecotate, 3,4-dimethylbromobenzene as the aryl halide, andthiomorpholine as the secondary amine utilizing general procedures A andB described above. ¹H NMR (300 MHz, CDCl₃) ¹H NMR (CDCl₃) δ 7.01 (d,J=7.8 Hz, 1H), 6.76 (d, J=2.3 Hz, 1H), 6.70 (dd, J=2.3, 7.8 Hz, 1H),3.90 (m, 2H), 3.80 (m, 2H), 2.96 (m, 1H), 2.89 (m,1H), 2.71-2.50 (m,7H), 2.23 (s, 3H), 2.18 (s, 3H), 2.04 (dd, J=2.6, 12.2 Hz, 1H), 1.93(dd, J=3.3, 12.3 Hz, 1H), 1.80 (m,1H), 1.76 (m, 1H). ESI MS: 319.4(MH⁺).

EXAMPLES 7-130

Using the methods and procedures of the schemes and examples, above, thecompounds in Table 1 were synthesized. TABLE 1 Compound Structure 7

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BIOLOGICAL EXAMPLES

The compounds of the invention were tested using a high throughput VR-1FLIPR assay.

-   -   Human VR₁ Functional Assay

The functional activity of the test compounds was determined bymeasuring changes in intracellular calcium concentration using aCa⁺⁺-sensitive fluorescent dye and FLIPR™ technology. Increases in Ca⁺⁺concentration were readily detected upon challenge with resiniferatoxin(RTX). A431 cells expressing human VR1 were seeded on polystyrene384-well back walled clear bottom assay plates coated with collagen andincubated for 3-4 hours at 37° C. with 5% CO₂ in DMEM. Plates wereloaded with 15 μL of 2× Dye Solution, incubated for 1-1.5 hours andsubsequently tested for agonist-induced increases in intracellular Ca²⁺levels using FLIPR™ technology. Cells were challenged with testcompounds (at varying concentrations) and intracellular Ca⁺⁺ wasmeasured prior to the addition of resiniferatoxin to all wells to elicit˜80% maximal response. EC₅₀ or IC₅₀ values were determined fromdose-response studies.

The compounds of the invention were found to be potent modulators ofVR1, and in particular, EC₅₀ values were measured as tabulated in Table2, below. TABLE 2 Compound EC₅₀ (μM) 1 0.23 2 0.24 3 0.27 4 0.27 5 0.336 0.34 7 0.76 8 0.91 9 1.04 10 1.3 11 1.42 12 1.50 13 1.59 14 1.64 151.85 16 1.89 17 1.91 18 1.97 19 2.00 20 2.05 21 2.20 22 2.30 23 2.80 243.10 25 3.20 26 3.26 27 3.53 28 3.70 29 3.80 30 3.80 31 4.00 32 4.10 334.10 34 4.37 35 4.60 36 5.20 37 5.40 38 7.84

1. A compound of formula (I)

wherein

is a 4 to 8 membered cyclic heteroalkyl group bonded to the rest of themolecule through a ring nitrogen atom and optionally containing 1-2heteroatoms in addition to said ring nitrogen atom, wherein the optional1-2 additional heteroatoms are independently selected from the groupconsisting of N, O and S; or a 5 to 10 membered heteroaryl group bondedto the rest of the molecule through a ring nitrogen atom and selectedfrom the group consisting of dihydroquinoline, tetrahydroquinoline,dihydroisoquinoline, tetrahydroisoquinoline, benzimidazole, imidazole,imidazoline, indazole, indole, indoline, isoindole, isoindoline,pyrazole, pyrrole, and triazole; Y is bonded to

at a substitutable atom and is independently selected from the groupconsisting of hydrogen; hydroxyl; R¹; R¹O—; R¹S—; CF₃O—; R¹S(O)—; R¹SO₂;-LCOX; C₆₋₁₀aryl; a 3 to 7 membered cyclic heteroalkanyl containing from1 to 3 heteroatoms wherein said heteroatoms independently are N, O or S;and a 5 to 10 membered heteroaryl selected from the group consisting ofbenzofuran, benzimidazole, benzisoxazole, benzthiazole, benzothiophene,benzoxazole, cinnoline, furan, imidazole, imidazoline, indazole, indole,indoline, indolizine, isobenzofuran, isoindole, isoindoline,isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole,oxazole, pthalazine, pteridine, purine, pyran, pyrazine, pyrazole,pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinoline,quinolizine, quinazoline, quinoxaline, tetrazole, thiadiazole, thiazole,thiophene, triazine, and triazole; n is an integer from 0 to 4; Ar isphenyl; naphthyl; a 5-6 membered heteroaryl ring selected from the groupconsisting of furan, imidazole, isothiazole, isoxazole, oxadiazole,oxazole, pyran, pyrazine, pyrazole, pyridazine, pyrrole, tetrazole,thiadiazole, triazine, and triazole; or a fused 5,6 or 6,6 heteroarylselected from the group consisting of benzimidazole, benzisoxazole,benzofuran, benzoxazole, benzthiazole, benzothiophene, cinnoline,indazole, indole, indoline, indolizine, isobenzofuran, isoindole,isoindoline, isoquinoline, naphthyridine, pthalazine, pteridine,pyrrolizine, quinoline, and quinolizine; wherein Ar is optionallysubstituted with one to four substituents independently selected fromthe group consisting of halogen; R¹; fluorinated C₁₋₁₀alkyl; phenyl;amino; cyano; fluorinated C₁₋₁₀alkyl; a 3 membered cyclic heteroalkylcontaining 1 heteroatom that is N, O or S wherein said 3 membered cyclicheteroalkyl is optionally substituted with a substituent that ishalogen, R¹, fluorinated C₁₋₁₀alkyl, amino, cyano, R¹O—, R¹S—, R¹SO₂—,R¹S(O)—, R¹SO₂NH—, or -LCOX; a 4 to 5 membered cyclic heteroalkylcontaining 1-3 heteroatoms that independently are N, O or S wherein said4 to 5 membered cyclic heteroalkyl is optionally substituted with 1 to 2substituents that independently are halogen, R¹, fluorinated C₁₋₁₀alkyl,amino, cyano, CF₃O—, R¹O—, R¹S—, R¹SO₂—, R¹S(O)—, R¹SO₂NH—, or -LCOX; a6 to 7 membered cyclic heteroalkyl containing 1-3 heteroatoms thatindependently are N, O or S wherein said 6 to 7 membered cyclicheteroalkyl is optionally substituted with 1 to 3 substituents thatindependently are halogen, R¹, fluorinated C₁₋₁₀alkyl, amino, cyano,R¹O—, R¹S—, R¹SO₂—, R¹S(O)—, R¹SO₂NH—, or -LCOX; a heteroaryl whereinsaid heteroaryl is cinnoline, furan, imidazole, indazole, indole,indoline, indolizine, isobenzofuran, isoindole, isoindoline,isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole,oxazole, pthalazine, pteridine, pyran, pyrazine, pyrazole, pyridazine,pyridine, pyrimidine, pyrrole, pyrrolizine, quinoline, quinolizine,quinazoline, quinoxaline, tetrazole, thiadiazole, triazine, or triazolewherein said heteroaryl is optionally substituted with 1 to 3substituents that independently are halogen, R¹, fluorinated C₁₋₁₀alkyl,amino, cyano, CF₃O—, R¹O—, R¹S—, R¹SO₂—, R¹S(O)—, R¹SO₂NH—, or -LCOX;;hydroxyl;; R¹O—; R¹S—; R¹SO₂—; R¹S(O)—; R¹SO₂NH—; -LCOX; and C₆₋₁₀aryl;R¹ is C₁₋₁₀alkyl; L is —NH—, a direct bond, —O—, or —CH₂—; X is H, R¹,HO, R¹O—, R¹S—, —NH₂, R¹NH—, or (R¹)₂N—; and enantiomers, diastereomers,tautomers, solvates, and pharmaceutically acceptable salts thereof.
 2. Acompound according to claim 1 wherein

is thiomorpholin-4-yl.
 3. A compound according to claim 1 wherein

is morpholin-4-yl.
 4. A compound according to claim 1 wherein

is piperidin-1-yl.
 5. A compound according to claim 1 wherein

is thiazolidin-3-yl.
 6. A compound according to claim 1 wherein

is azepan-1-yl.
 7. A compound according to claim 1 wherein

is piperazin-1-yl.
 8. A compound according to claim 1 wherein

is pyrrolidin-1-yl.
 9. A compound according to claim 1 wherein Y is OH.10. A compound according to claim 1 wherein Y is methylcarbonyl.
 11. Acompound according to claim 1 wherein Y is methyl.
 12. A compoundaccording to claim 1 wherein n is
 0. 13. A compound according to claim 1wherein n is
 1. 14. A compound according to claim 1 wherein Ar isphenyl.
 15. A compound according to claim 1 wherein Ar is naphthyl. 16.A compound according to claim 1 wherein Ar is substituted with 1-2substituents independently selected from the group consisting ofhalogen, R¹, R¹O—, fluorinated C₁₋₁₀alkyl, phenyl, and fluorinatedC₁₋₁₀alkyl.
 17. A compound according to claim 1 wherein Ar issubstituted with 1-2 substituents independently selected from the groupconsisting of methyl, phenyl, CF₂—, F, and CH₃O—.
 18. A compoundaccording to claim 1 wherein Ar is phenyl optionally substituted with1-2 substituents independently selected from the group consisting ofhalogen, R¹, R¹O—, fluorinated C₁₋₁₀alkyl, phenyl, and fluorinatedC₁₋₁₀alkyl.
 19. A compound according to claim 1 wherein

is piperidin-1-yl and n is
 1. 20. A compound according to claim 1wherein n is 1 and Y is OH or methylcarbonyl.
 21. A compound accordingto claim 1 wherein Ar is biphenyl, methylphenyl or dimethylphenyl.
 22. Acompound according to claim 1 selected from the group consisting of:Thiomorpholin-4-yl-(1-o-tolyl-piperidin-4-yl)-methanone;[1-(2,3-Dimethyl-phenyl)-piperidin-4-yl]-(4-hydroxy-piperidin-1-yl)-methanone;(1-Biphenyl-3-yl-piperidin-4-yl)-morpholin-4-yl-methanone;[1-(3-Fluoro-4-methyl-phenyl)-piperidin-4-yl]-thiomorpholin-4-yl-methanoneMorpholin-4-yl-[1-(3-trifluoromethyl-phenyl)-piperidin-4-yl]-methanone;[1-(3,4-Dimethyl-phenyl)-piperidin-4-yl]-thiomorpholin-4-yl-methanone;[1-(2,3-Dimethyl-phenyl)-piperidin-4-yl]-thiomorpholin-4-yl-methanone;[1-(3,4-Dimethyl-phenyl)-piperidin-4-yl]-(4-hydroxy-piperidin-1-yl)-methanone;[1-(3,4-Dimethyl-phenyl)-piperidin-4-yl]-piperidin-1-yl-methanone;[1-(3-Fluoro-4-methyl-phenyl)-piperidin-4-yl]-piperidin-1-yl-methanone;(4-Hydroxy-piperidin-1-yl)-(1-o-tolyl-piperidin-4-yl)-methanone;[1-(3,4-Dimethyl-phenyl)-piperidin-4-yl]-morpholin-4-yl-methanone;Morpholin-4-yl-(1-o-tolyl-piperidin-4-yl)-methanone;[1-(2,3-Dimethyl-phenyl)-piperidin-4-yl]-piperidin-1-yl-methanone;[1-(3,5-Difluoro-phenyl)-piperidin-4-yl]-morpholin-4-yl-methanone;[1-(2,3-Dimethyl-phenyl)-piperidin-4-yl]-thiazolidin-3-yl-methanone;(1-Naphthalen-1-yl-piperidin-4-yl)-piperidin-1-yl-methanone;[1-(3,5-Difluoro-phenyl)-piperidin-4-yl]-thiomorpholin-4-yl-methanone;[1-(3-Fluoro-4-methyl-phenyl)-piperidin-4-yl]-morpholin-4-yl-methanone;[1-(3,5-Difluoro-phenyl)-piperidin-4-yl]-piperidin-1-yl-methanone;(1-Biphenyl-3-yl-piperidin-4-yl)-thiomorpholin-4-yl-methanone;[1-(3-Fluoro-4-methyl-phenyl)-piperidin-4-yl]-(4-hydroxy-piperidin-1-yl)-methanone;[1-(3,5-Difluoro-phenyl)-piperidin-4-yl]-(4-hydroxy-piperidin-1-yl)-methanone;(1-Naphthalen-1-yl-piperidin-4-yl)-thiazolidin-3-yl-methanone;Azepan-1-yl-(1-o-tolyl-piperidin-4-yl)-methanone;Piperidin-1-yl-(1-o-tolyl-piperidin-4-yl)-methanone;[1-(3-Methoxy-phenyl)-piperidin-4-yl]-morpholin-4-yl-methanone;Piperidin-1-yl-[1-(3-trifluoromethyl-phenyl)-piperidin-4-yl]-methanone;Piperidin-1-yl-(1-m-tolyl-piperidin-4-yl)-methanone;1-[4-(1-Biphenyl-3-yl-piperidine-4-carbonyl)-piperazin-1-yl]-ethanone;1-{4-[1-(2,3-Dimethyl-phenyl)-piperidine-4-carbonyl]-piperazin-1-yl}-ethanone;Morpholin-4-yl-(1-m-tolyl-piperidin-4-yl)-methanone;(1-Biphenyl-3-yl-piperidin-4-yl)-piperidin-1-yl-methanone;[1-(3-Methoxy-phenyl)-piperidin-4-yl]-thiomorpholin-4-yl-methanone;[1-(2,3-Dimethyl-phenyl)-piperidin-4-yl]-(2,6-dimethyl-piperidin-1-yl)-methanone;[1-(2,3-Dimethyl-phenyl)-piperidin-4-yl]-(3-hydroxy-pyrrolidin-1-yl)-methanone;Thiazolidin-3-yl-(1-o-tolyl-piperidin-4-yl)-methanone;Pyrrolidin-1-yl-(1-o-tolyl-piperidin-4-yl)-methanone;(1-Isoquinolin-1-yl-piperidin-4-yl)-morpholin-4-yl-methanone;[1-(3,6-Dimethyl-pyrazin-2-yl)-piperidin-4-yl]-morpholin-4-yl-methanone;Morpholin-4-yl-(1-naphthalen-1-yl-piperidin-4-yl)-methanone;[1-(2,3-Dimethyl-phenyl)-piperidin-4-yl]-morpholin-4-yl-methanone;Morpholin-4-yl-[1-(3-trifluoromethyl-phenyl)-piperidin-4-yl]-methanone;(1-Naphthalen-1-yl-piperidin-4-yl)-thiomorpholin-4-yl-methanone;(1-Isoquinolin-1-yl-piperidin-4-yl)-thiomorpholin-4-yl-methanone;Thiomorpholin-4-yl-(1-m-tolyl-piperidin-4-yl)-methanone;Thiomorpholin-4-yl-[1-(3-trifluoromethyl-phenyl)-piperidin-4-yl]-methanone;[1-(3,6-Dimethyl-pyrazin-2-yl)-piperidin-4-yl]-thiomorpholin-4-yl-methanone;(4-Hydroxy-piperidin-1-yl)-(1-naphthalen-1-yl-piperidin-4-yl)-methanone;(4-Hydroxy-piperidin-1-yl)-(1-isoquinolin-1-yl-piperidin-4-yl)-methanone;(1-Biphenyl-3-yl-piperidin-4-yl)-(4-hydroxy-piperidin-1-yl)-methanone;(1-Isoquinolin-1-yl-piperidin-4-yl)-piperidin-1-yl-methanone;Piperidin-1-yl-(1-m-tolyl-piperidin-4-yl)-methanone;[1-(3-Methoxy-phenyl)-piperidin-4-yl]-piperidin-1-yl-methanone;Piperidin-1-yl-[1-(3-trifluoromethyl-phenyl)-piperidin-4-yl]-methanone;[1-(3,6-Dimethyl-pyrazin-2-yl)-piperidin-4-yl]-piperidin-1-yl-methanone;[1-(2,3-Dimethyl-phenyl)-piperidin-4-yl]-pyrrolidin-1-yl-methanone;(1-Naphthalen-1-yl-piperidin-4-yl)-pyrrolidin-1-yl-methanone;(1-Biphenyl-3-yl-piperidin-4-yl)-pyrrolidin-1-yl-methanone;(1-Isoquinolin-1-yl-piperidin-4-yl)-pyrrolidin-1-yl-methanone;[1-(3-Fluoro-4-methyl-phenyl)-piperidin-4-yl]-pyrrolidin-1-yl-methanone;Pyrrolidin-1-yl-(1-m-tolyl-piperidin-4-yl)-methanone;[1-(3,5-Difluoro-phenyl)-piperidin-4-yl]-pyrrolidin-1-yl-methanone;[1-(3,6-Dimethyl-pyrazin-2-yl)-piperidin-4-yl]-pyrrolidin-1-yl-methanone;[1-(3-Methoxy-phenyl)-piperidin-4-yl]-pyrrolidin-1-yl-methanone;Pyrrolidin-1-yl-[1-(3-trifluoromethyl-phenyl)-piperidin-4-yl]-methanone;(1-Biphenyl-3-yl-piperidin-4-yl)-thiazolidin-3-yl-methanone;(1-Isoquinolin-1-yl-piperidin-4-yl)-thiazolidin-3-yl-methanone;Thiazolidin-3-yl-(1-m-tolyl-piperidin-4-yl)-methanone;[1-(3,5-Difluoro-phenyl)-piperidin-4-yl]-thiazolidin-3-y-methanone;[1-(3,6-Dimethyl-pyrazin-2-yl)-piperidin-4-yl]-thiazolidin-3-yl-methanone;[1-(3-Methoxy-phenyl)-piperidin-4-yl]-thiazolidin-3-yl-methanone;Thiazolidin-3-yl-[1-(3-trifluoromethyl-phenyl)-piperidin-4-yl]-methanone;(2,6-Dimethyl-piperidin-1-yl)-(1-naphthalen-1-yl-piperidin-4-yl)-methanone;(1-Biphenyl-3-yl-piperidin-4-yl)-(2,6-dimethyl-piperidin-1-yl)-methanone;(2,6-Dimethyl-piperidin-1-yl)-(1-o-tolyl-piperidin-4-yl)-methanone;(2,6-Dimethyl-piperidin-1-yl)-(1-m-tolyl-piperidin-4-yl)-methanone;[1-(3,5-Difluoro-phenyl)-piperidin-4-yl]-(2,6-dimethyl-piperidin-1-yl)-methanone;(2,6-Dimethyl-piperidin-1-yl)-[1-(3,6-dimethyl-pyrazin-2-yl)-piperidin-4-yl]-methanone;(2,6-Dimethyl-piperidin-1-yl)-[1-(3-methoxy-phenyl)-piperidin-4-y]-methanone;(2,6-Dimethyl-piperidin-1-yl)-[1-(3-trifluoromethyl-phenyl)-piperidin-4-yl]-methanone;(3-Hydroxy-pyrrolidin-1-yl)-(1-naphthalen-1-yl-piperidin-4-yl)-methanone;(1-Biphenyl-3-yl-piperidin-4-yl)-(3-hydroxy-pyrrolidin-1-yl)-methanone;(3-Hydroxy-pyrrolidin-1-yl)-(1-isoquinolin-1-yl-piperidin-4-yl)-methanone;(3-Hydroxy-pyrrolidin-1-yl)-(1-o-tolyl-piperidin-4-yl)-methanone;[1-(3-Fluoro-4-methyl-phenyl)-piperidin-4-yl]-(3-hydroxy-pyrrolidin-1-yl)-methanone;[1-(3,6-Dimethyl-pyrazin-2-yl)-piperidin-4-yl]-(3-hydroxy-pyrrolidin-1-yl)-methanone;Azepan-1-yl-[1-(2,3-dimethyl-phenyl)-piperidin-4-yl]-methanone;Azepan-1-yl-(1-naphthalen-1-yl-piperidin-4-yl)-methanone;Azepan-1-yl-(1-biphenyl-3-yl-piperidin-4-yl)-methanone;Azepan-1-yl-(1-isoquinolin-1-yl-piperidin-4-yl)-methanone;Azepan-1-yl-[1-(3-fluoro-4-methyl-phenyl)-piperidin-4-yl]-methanone;Azepan-1-yl-(1-m-tolyl-piperidin-4-yl)-methanone;Azepan-1-yl-[1-(3,5-difluoro-phenyl)-piperidin-4-yl]-methanone;Azepan-1-yl-[1-(3-methoxy-phenyl)-piperidin-4-yl]-methanone;Azepan-1-yl-[1-(3-trifluoromethyl-phenyl)-piperidin-4-yl]-methanone;Azepan-1-yl-[1-(3,6-dimethyl-pyrazin-2-yl)-piperidin-4-yl]-methanone;1-[4-(1-Isoquinolin-1-yl-piperidine-4-carbonyl)-piperazin-1-yl]-ethanone;1-[4-(1-o-Tolyl-piperidine-4-carbonyl)-piperazin-1-yl]-ethanone;1-{4-[1-(3-Fluoro-4-methyl-phenyl)-piperidine-4-carbonyl]-piperazin-1-yl)-ethanone;1-[4-(1-m-Tolyl-piperidine-4-carbonyl)-piperazin-1-yl]-ethanone;1-{4-[1-(3,5-Difluoro-phenyl)-piperidine-4-carbonyl]-piperazin-1-yl}-ethanone;1-{4-[1-(3-Methoxy-phenyl)-piperidine-4-carbonyl]-piperazin-1-yl}-ethanone;1-{4-[1-(3-Trifluoromethyl-phenyl)-piperidine-4-carbonyl]-piperazin-1-yl}-ethanone;1-{4-[1-(3,6-Dimethyl-pyrazin-2-yl)-piperidine-4-carbonyl]-piperazin-1-yl}-ethanone;1-[1-(2,3-Dimethyl-phenyl)-piperidine-4-carbonyl]-pyrrolidine-2-carboxylicacid amide;1-(1-Naphthalen-1-yl-piperidine-4-carbonyl)-pyrrolidine-2-carboxylicacid amide;1-(1-Biphenyl-3-yl-piperidine-4-carbonyl)-pyrrolidine-2-carboxylic acidamide;1-(1-Isoquinolin-1-yl-piperidine-4-carbonyl)-pyrrolidine-2-carboxylicacid amide; 1-(1-o-Tolyl-piperidine-4-carbonyl)-pyrrolidine-2-carboxylicacid amide;1-[1-(3-Fluoro-4-methyl-phenyl)-piperidine-4-carbonyl]-pyrrolidine-2-carboxylicacid amide; 1-(1-m-Tolyl-piperidine-4-carbonyl)-pyrrolidine-2-carboxylicacid amide;1-[1-(3-Methoxy-phenyl)-piperidine-4-carbonyl]-pyrrolidine-2-carboxylicacid amide;1-[1-(3-Trifluoromethyl-phenyl)-piperidine-4-carbonyl]-pyrrolidine-2-carboxylicacid amide;1-[1-(3,5-Difluoro-phenyl)-piperidine-4-carbonyl]-pyrrolidine-2-carboxylicacid amide;1-[1-(3,6-Dimethyl-pyrazin-2-yl)-piperidine-4-carbonyl]-pyrrolidine-2-carboxylicacid amide;Azetidin-1-yl-[1-(2,3-dimethyl-phenyl)-piperidin-4-yl]-methanone;Azetidin-1-yl-(1-naphthalen-1-yl-piperidin-4-yl)-methanone;Azetidin-1-yl-(1-isoquinolin-1-yl-piperidin-4-yl)-methanone;Azetidin-1-yl-(1-biphenyl-3-yl-piperidin-4-yl)-methanone;Azetidin-1-yl-(1-o-tolyl-piperidin-4-yl)-methanone;Azetidin-1-yl-[1-(3-fluoro-4-methyl-phenyl)-piperidin-4-yl]-methanone;Azetidin-1-yl-(1-m-tolyl-piperidin-4-yl)-methanone;Azetidin-1-yl-[1-(3-methoxy-phenyl)-piperidin-4-yl]-methanone;Azetidin-1-yl-[1-(3-trifluoromethyl-phenyl)-piperidin-4-yl]-methanone;Azetidin-1-yl-[1-(3,5-difluoro-phenyl)-piperidin-4-yl]-methanone;Azetidin-1-yl-[1-(3,6-dimethyl-pyrazin-2-yl)-piperidin-4-yl]-methanone;(2,6-Dimethyl-morpholin-4-yl)-[1-(2,3-dimethyl-phenyl)-piperidin-4-yl]-methanone;(3,4-Dihydro-2H-quinolin-1-yl)-[1-(2,3-dimethyl-phenyl)-piperidin-4-yl]-methanone;[1-(2,3-Dimethyl-phenyl)-piperidin-4-yl]-(4-ethyl-piperazin-1-yl)-methanone.